tbuckley/cabot-search huggingface dataset:
Evaluation of Clinical and Safety Outcomes of Neoadjuvant Immunotherapy Combined With Chemotherapy for Patients With Resectable Esophageal Cancer
Authors: Fan Ge, Zhenyu Huo, Xiuyu Cai, Qiyuan Hu, Wenhao Chen, Guo Lin, Ran Zhong, Zhending You, Rui Wang, Yi Lu, Runchen Wang, Qinhong Huang, Haotian Zhang, Aiqi Song, Caichen Li, Yaokai Wen, Yu Jiang, Hengrui Liang, Jianxing He, Wenhua Liang, Jun Liu
Journal: JAMA Network Open (2022)

Importance A considerable number of clinical trials of neoadjuvant immunotherapy for patients with resectable esophageal cancer are emerging. However, systematic evaluations of these studies are lacking. Objective To provide state-of-the-art evidence and normative theoretical support for neoadjuvant immunotherapy for locally advanced resectable esophageal cancer. Data Sources PubMed, Embase, Cochrane Library, and ClinicalTrials.gov databases were searched for relevant original articles and conference proceedings that were published in English through April 1, 2022. Study Selection Published phase 2 or 3 clinical trials that included patients with resectable stage I to IV esophageal cancer who received immune checkpoint inhibitors (ICIs) before surgery as monotherapy or in combination with other therapies. Data Extraction and Synthesis The Preferred Reporting Items for Systematic Reviews and Meta-analyses and the Meta-analysis of Observational Studies in Epidemiology guidelines for meta-analysis were followed to extract data. A random-effects model was adopted if the heterogeneity was significant ( I 2 statistic &amp;amp;gt;50%); otherwise, the common-effects model was used. Data analyses were conducted from April 2 to 8, 2022. Main Outcomes and Measures Pathological complete response (pCR) rate and major pathological response (MPR) rate were considered to be the primary outcomes calculated for the clinical outcomes of neoadjuvant immunotherapy. Incidence of treatment-related severe adverse events was set as the major measure for the safety outcome. The rate of R0 surgical resection was summarized. Subgroup analyses were conducted according to histologic subtype and ICI types. Results A total of 27 clinical trials with 815 patients were included. Pooled rates were 31.4% (95% CI, 27.6%-35.3%) for pCR and 48.9% (95% CI, 42.0-55.9%) for MCR in patients with esophageal cancer. In terms of safety, the pooled incidence of treatment-related severe adverse events was 26.9% (95% CI, 16.7%-38.3%). Most patients achieved R0 surgical resection (98.6%; 95% CI, 97.1%-99.6%). Regarding histologic subtypes, the pooled pCR rates were 32.4% (95% CI, 28.2%-36.8%) in esophageal squamous cell carcinoma and 25.2% (95% CI, 16.3%-35.1%) in esophageal adenocarcinoma. The pooled MPR rate was 49.4% (95% CI, 42.1%-56.7%) in esophageal squamous cell carcinoma. Conclusions and Relevance This study found that neoadjuvant immunotherapy with chemotherapy had promising clinical and safety outcomes for patients with resectable esophageal cancer. Randomized clinical trials with long-term follow-up are warranted to validate the findings and benefits of ICIs.
Concordance Between Patient-Reported Health Data and Electronic Health Data in the ADAPTABLE Trial
Authors: Emily C. O’Brien, Hillary Mulder, W. Schuyler Jones, Bradley G. Hammill, Amber Sharlow, Adrian F. Hernandez, Lesley H. Curtis
Journal: JAMA Cardiology (2022)

Patient-reported health data can facilitate clinical event capture in pragmatic clinical trials. However, few data are available on the fitness for use of patient-reported data in large-scale health research.To evaluate the concordance of a set of variables reported by patients and available in the electronic health record as part of a pragmatic clinical trial.Data from ADAPTABLE (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-term Effectiveness), a pragmatic clinical trial, were used in a concordance substudy of a comparative effectiveness research trial. The trial randomized 15 076 patients with existing atherosclerotic cardiovascular disease in a 1:1 ratio to low- or high-dose aspirin from April 2016 through June 30, 2019.Concordance of data was evaluated from 4 domains (demographic characteristics, encounters, diagnoses, and procedures) present in 2 data sources: patient-reported data captured through an online portal and data from electronic sources (electronic health record data). Overall agreement, sensitivity, specificity, positive predictive value, negative predictive value, and κ statistics with 95% CIs were calculated using patient report as the criterion standard for demographic characteristics and the electronic health record as the criterion standard for clinical outcomes.Of 15 076 patients with complete information, the median age was 67.6 years (range, 21-99 years), and 68.7% were male. With the use of patient-reported data as the criterion standard, agreement (κ) was high for Black and White race and ethnicity but only moderate for current smoking status. Electronic health record data were highly specific (99.6%) but less sensitive (82.5%) for Hispanic ethnicity. Compared with electronic health record data, patient report of clinical end points had low sensitivity for myocardial infarction (33.0%), stroke (34.2%), and major bleeding (36.6%). Positive predictive value was similarly low for myocardial infarction (40.7%), stroke (38.8%), and major bleeding (21.9%). Coronary revascularization was the most concordant event by data source, with only moderate agreement (κ = 0.54) and positive predictive value. Agreement metrics varied by site for all demographic characteristics and several clinical events.In a concordance substudy of a large, pragmatic comparative effectiveness research trial, sensitivity and chance-corrected agreement of patient-reported data captured through an online portal for cardiovascular events were low to moderate. Findings suggest that additional work is needed to optimize integration of patient-reported health data into pragmatic research studies.ClinicalTrials.gov Identifier: NCT02697916.
Intravenous administration of viral vectors expressing prostate cancer antigens enhances the magnitude and functionality of CD8+ T cell responses
Authors: Antonella Vardeu, Charlotte Davis, Ian McDonald, Guilherme Stahlberg, Barsha Thapa, Kinga Piotrowska, Margaret A Marshall, Thomas Evans, Vicky Wheeler, Sarah Sebastian, Katie Anderson
Journal: Journal for ImmunoTherapy of Cancer (2022)

The use of immunotherapeutic vaccination in prostate cancer is a promising approach that likely requires the induction of functional, cytotoxic T cells . The experimental approach described here uses a well-studied adenovirus-poxvirus heterologous prime-boost regimen, in which the vectors encode a combination of prostate cancer antigens, with the booster dose delivered by either the intravenous or intramuscular (IM) route. This prime-boost regimen was investigated for antigen-specific CD8+ T cell induction.The coding sequences for four antigens expressed in prostate cancer, 5T4, PSA, PAP, and STEAP1, were inserted into replication-incompetent chimpanzee adenovirus Oxford 1 (ChAdOx1) and into replication-deficient modified vaccinia Ankara (MVA). In four strains of mice, ChAdOx1 prime was delivered intramuscularly, with an MVA boost delivered by either IM or intravenous routes. Immune responses were measured in splenocytes using ELISpot, multiparameter flow cytometry, and a targeted in vivo killing assay.The prime-boost regimen was highly immunogenic, with intravenous administration of the boost resulting in a sixfold increase in the magnitude of antigen-specific T cells induced and increased in vivo killing relative to the intramuscular boosting route. Prostate-specific antigen (PSA)-specific responses were dominant in all mouse strains studied (C57BL/6, BALBc, CD-1 and HLA-A2 transgenic).This quadrivalent immunotherapeutic approach using four antigens expressed in prostate cancer induced high magnitude, functional CD8+ T cells in murine models. The data suggest that comparing the intravenous versus intramuscular boosting routes is worthy of investigation in humans.
Identification of natural product 3, 5-diiodotyrosine as APOBEC3B inhibitor to prevent somatic mutation accumulation and cancer progression
Authors: Chunxia Chen, Xinghua Sui, Haoming Ning, Yixuan Sun, Jiangfeng Du, Xiaotong Chen, Xiuman Zhou, Guanyu Chen, Wenhui Shen, Liwei Pang, Xiaowen Zhou, Ranran Shi, Wanqiong Li, Hongfei Wang, Wenshan Zhao, Wenjie Zhai, Yuanming Qi, Yahong Wu, Yanfeng Gao
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background The development of cancer is largely dependent on the accumulation of somatic mutations, indicating the potential to develop cancer chemoprevention agents targeting mutation drivers. However, ideal cancer chemoprevention agents that can effectively inhibit the mutation drivers have not been identified yet. Methods The somatic mutation signatures and expression analyses of APOBEC3B were performed in patient with pan-cancer. The computer-aided screening and skeleton-based searching were performed to identify natural products that can inhibit the activity of APOBEC3B. 4-nitroquinoline-1-oxide (4-NQO)-induced spontaneous esophageal squamous cell carcinoma (ESCC) and azoxymethane/dextran sulfate sodium (AOM/DSS)-induced spontaneous colon cancer mouse models were conducted to investigate the influences of APOBEC3B inhibitor on the prevention of somatic mutation accumulation and cancer progression. Results Here, we discovered that the cytidine deaminase APOBEC3B correlated somatic mutations were widely observed in a variety of cancers, and its overexpression indicated poor survival. SMC247 (3, 5-diiodotyrosine), as a source of kelp iodine without side effects, could strongly bind APOBEC3B (K D =65 nM) and effectively inhibit its deaminase activity (IC 50 =1.69 µM). Interestingly, 3, 5-diiodotyrosine could significantly reduce the clusters of mutations, prevent the precancerous lesion progression, and prolong the survival in 4-NQO-induced spontaneous ESCC and AOM/DSS-induced spontaneous colon cancer mouse models. Furthermore, 3, 5-diiodotyrosine could reduce colitis, increase the proportion and function of T lymphocytes via IL-15 in tumor microenvironment. The synergistic cancer prevention effects were observed when 3, 5-diiodotyrosine combined with PD-1/PD-L1 blockade. Conclusions This is the first prove-of-concept study to elucidate that the natural product 3, 5-diiodotyrosine could prevent somatic mutation accumulation and cancer progression through inhibiting the enzymatic activity of APOBEC3B. In addition, 3, 5-diiodotyrosine could reduce the colitis and increase the infiltration and function of T lymphocytes via IL-15 in tumor microenvironment. 3, 5-diiodotyrosine combined with PD-1/PD-L1 blockade could elicit synergistic cancer prevention effects, indicating a novel strategy for both prevent the somatic mutation accumulation and the immune-suppressive microenvironment exacerbation.
Mental Health Care Utilization Among Children and Adolescents With a Firearm Injury
Authors: Elizabeth R. Oddo, Annie N. Simpson, Lizmarie Maldonado, Ashley B. Hink, Annie L. Andrews
Journal: JAMA Surgery (2022)

Firearm injuries are a leading cause of morbidity and mortality among US children and adolescents. Despite evidence demonstrating mental health sequelae for children and adolescents who have experienced a firearm injury, little is known about mental health care utilization after a firearm injury.
DragNet: Learning-based deformable registration for realistic cardiac MR sequence generation from a single frame
Authors: Arezoo Zakeri, Alireza Hokmabadi, Ning Bi, Isuru Wijesinghe, Michael G. Nix, Steffen E. Petersen, Alejandro F. Frangi, Zeike A. Taylor, Ali Gooya
Journal: Medical Image Analysis (2022)

Deformable image registration (DIR) can be used to track cardiac motion. Conventional DIR algorithms aim to establish a dense and non-linear correspondence between independent pairs of images. They are, nevertheless, computationally intensive and do not consider temporal dependencies to regulate the estimated motion in a cardiac cycle. In this paper, leveraging deep learning methods, we formulate a novel hierarchical probabilistic model, termed DragNet, for fast and reliable spatio-temporal registration in cine cardiac magnetic resonance (CMR) images and for generating synthetic heart motion sequences. DragNet is a variational inference framework, which takes an image from the sequence in combination with the hidden states of a recurrent neural network (RNN) as inputs to an inference network per time step. As part of this framework, we condition the prior probability of the latent variables on the hidden states of the RNN utilised to capture temporal dependencies. We further condition the posterior of the motion field on a latent variable from hierarchy and features from the moving image. Subsequently, the RNN updates the hidden state variables based on the feature maps of the fixed image and the latent variables. Different from traditional methods, DragNet performs registration on unseen sequences in a forward pass, which significantly expedites the registration process. Besides, DragNet enables generating a large number of realistic synthetic image sequences given only one frame, where the corresponding deformations are also retrieved. The probabilistic framework allows for computing spatio-temporal uncertainties in the estimated motion fields. Our results show that DragNet performance is comparable with state-of-the-art methods in terms of registration accuracy, with the advantage of offering analytical pixel-wise motion uncertainty estimation across a cardiac cycle and being a motion generator. We will make our code publicly available.
Dynamics of T cell repertoire renewal following autologous hematopoietic stem cell transplantation in multiple sclerosis
Authors: Josefine Ruder, María José Docampo, Jordan Rex, Simon Obahor, Reza Naghavian, Antonia M.S. Müller, Urs Schanz, Ilijas Jelcic, Roland Martin
Journal: Science Translational Medicine (2022)

Autologous hematopoietic stem cell transplantation (aHSCT) is a highly effective treatment of multiple sclerosis (MS). It depletes autoreactive cells and subsequently renews adaptive immune cells. The possible proinflammatory potential of surviving T cells early after aHSCT has not been studied. Here, we examined the dynamics of new and surviving T cells in 27 patients after aHSCT by multidimensional flow cytometry, T cell receptor (TCR) sequencing, specificity testing, telomere length profiling, and HLA genotyping. Early after aHSCT, naïve T cells are barely detectable, whereas effector memory (EM) T cells quickly reconstitute to pre-aHSCT values. EM CD4 + T cells early after aHSCT have shorter telomeres, have higher expression of senescence and exhaustion markers, and proliferate less than those before aHSCT. We find a median TCR repertoire overlap of 26% between the early post-aHSCT EM CD4 + T cells and pre-aHSCT, indicating persistence of EM CD4 + T cells early after transplantation. The EM CD4 + TCR repertoire overlap declines to 15% at 12 months after aHSCT, whereas the naïve TCR repertoire entirely renews. HLA-DR–associated EM CD4 + T cell reactivity toward MS-related antigens decreased after aHSCT, whereas reactivity toward EBV increased. Our data show substantial survival of pre-aHSCT EM CD4 + T cells early after transplantation but complete renewal of the T cell repertoire by nascent T cells later.
ARL13B promotes angiogenesis and glioma growth by activating VEGFA-VEGFR2 signaling
Authors: Limin Chen, Xinsheng Xie, Tiantian Wang, Linlin Xu, Zhenyu Zhai, Haibin Wu, Libin Deng, Quqin Lu, Zhengjun Chen, Xiao Yang, Hua Lu, Ye-Guang Chen, Shiwen Luo
Journal: Neuro-Oncology (2022)

Tumor angiogenesis is essential for solid tumor progression, invasion and metastasis. The aim of this study was to identify potential signaling pathways involved in tumor angiogenesis.Genetically engineered mouse models were used to investigate the effects of endothelial ARL13B(ADP-ribosylation factor-like GTPase 13B) over-expression and deficiency on retinal and cerebral vasculature. An intracranially transplanted glioma model and a subcutaneously implanted melanoma model were employed to examine the effects of ARL13B on tumor growth and angiogenesis. Immunohistochemistry was used to measure ARL13B in glioma tissues, and scRNA-seq was used to analyze glioma and endothelial ARL13B expression. GST-fusion protein-protein interaction and co-immunoprecipitation assays were used to determine the ARL13B-VEGFR2 interaction. Immunobloting, qPCR, dual-luciferase reporter assay and functional experiments were performed to evaluate the effects of ARL13B on VEGFR2 activation.Endothelial ARL13B regulated vascular development of both the retina and brain in mice. Also, ARL13B in endothelial cells regulated the growth of intracranially transplanted glioma cells and subcutaneously implanted melanoma cells by controlling tumor angiogenesis. Interestingly, this effect was attributed to ARL13B interaction with VEGFR2, through which ARL13B regulated the membrane and ciliary localization of VEGFR2 and consequently activated its downstream signaling in endothelial cells. Consistent with its oncogenic role, ARL13B was highly expressed in human gliomas, which was well correlated with the poor prognosis of glioma patients. Remarkably, ARL13B, transcriptionally regulated by ZEB1, enhanced the expression of VEGFA by activating Hedgehog signaling in glioma cells.ARL13B promotes angiogenesis and tumor growth by activating VEGFA-VEGFR2 signaling. Thus, targeting ARL13B might serve as a potential approach for developing an anti-glioma or anti-melanoma therapy.
Targeting cancer glycosylation repolarizes tumor-associated macrophages allowing effective immune checkpoint blockade
Authors: Michal A. Stanczak, Natalia Rodrigues Mantuano, Nicole Kirchhammer, David E. Sanin, Francis Jacob, Ricardo Coelho, Arun V. Everest-Dass, Jinyu Wang, Marcel P. Trefny, Gianni Monaco, Anne Bärenwaldt, Melissa A. Gray, Adam Petrone, Abhishek S. Kashyap, Katharina Glatz, Benjamin Kasenda, Karl Normington, James Broderick, Li Peng, Oliver M.T. Pearce, Erika L. Pearce, Carolyn R. Bertozzi, Alfred Zippelius, Heinz Läubli
Journal: Science Translational Medicine (2022)

Immune checkpoint blockade (ICB) has substantially improved the prognosis of patients with cancer, but the majority experiences limited benefit, supporting the need for new therapeutic approaches. Up-regulation of sialic acid–containing glycans, termed hypersialylation, is a common feature of cancer-associated glycosylation, driving disease progression and immune escape through the engagement of Siglec receptors on tumor-infiltrating immune cells. Here, we show that tumor sialylation correlates with distinct immune states and reduced survival in human cancers. The targeted removal of Siglec ligands in the tumor microenvironment, using an antibody-sialidase conjugate, enhanced antitumor immunity and halted tumor progression in several murine models. Using single-cell RNA sequencing, we revealed that desialylation repolarized tumor-associated macrophages (TAMs). We also identified Siglec-E as the main receptor for hypersialylation on TAMs. Last, we found that genetic and therapeutic desialylation, as well as loss of Siglec-E, enhanced the efficacy of ICB. Thus, therapeutic desialylation represents an immunotherapeutic approach to reshape macrophage phenotypes and augment the adaptive antitumor immune response.
Hormonal therapies up-regulate MANF and overcome female susceptibility to immune checkpoint inhibitor myocarditis
Authors: Yaohua Zhang, Chengcao Sun, Yajuan Li, Juan Qin, Kaushik Amancherla, Ying Jing, Qingsong Hu, Ke Liang, Zhao Zhang, Youqiong Ye, Lisa A. Huang, Tina K. Nguyen, Sergey D. Egranov, Zilong Zhao, Andrew Wu, Yutao Xi, Jun Yao, Mien-Chie Hung, George A. Calin, Jie Cheng, Bora Lim, Lorenz H. Lehmann, Joe-Elie Salem, Douglas B. Johnson, Michael A. Curran, Dihua Yu, Leng Han, Radbod Darabi, Liuqing Yang, Javid J. Moslehi, Chunru Lin
Journal: Science Translational Medicine (2022)

Immune checkpoint inhibitors (ICIs) have been increasingly used in combination for cancer treatment but are associated with myocarditis. Here, we report that tumor-bearing mice exhibited response to treatment with combinatorial anti–programmed cell death 1 and anti–cytotoxic T lymphocyte antigen–4 antibodies but also presented with cardiovascular toxicities observed clinically with ICI therapy, including myocarditis and arrhythmia. Female mice were preferentially affected with myocarditis compared to male mice, consistent with a previously described genetic model of ICI myocarditis and emerging clinical data. Mechanistically, myocardial tissue from ICI-treated mice, the genetic mouse model, and human heart tissue from affected patients with ICI myocarditis all exhibited down-regulation of MANF (mesencephalic astrocyte–derived neurotrophic factor) and HSPA5 (heat shock 70-kDa protein 5) in the heart; this down-regulation was particularly notable in female mice. ICI myocarditis was amplified by heart-specific genetic deletion of mouse Manf and was attenuated by administration of recombinant MANF protein, suggesting a causal role. Ironically, both MANF and HSPA5 were transcriptionally induced by liganded estrogen receptor β and inhibited by androgen receptor. However, ICI treatment reduced serum estradiol concentration to a greater extent in female compared to male mice. Treatment with an estrogen receptor β–specific agonist and androgen depletion therapy attenuated ICI-associated cardiac effects. Together, our data suggest that ICI treatment inhibits estradiol-dependent expression of MANF/HSPA5 in the heart, curtailing the cardiomyocyte response to immune injury. This endocrine-cardiac-immune pathway offers new insights into the mechanisms of sex differences in cardiac disease and may offer treatment strategies for ICI myocarditis.
Selective decrease of donor-reactive T <sub>regs</sub> after liver transplantation limits T <sub>reg</sub> therapy for promoting allograft tolerance in humans
Authors: Qizhi Tang, Joey Leung, Yani Peng, Alberto Sanchez-Fueyo, Juan-Jose Lozano, Alice Lam, Karim Lee, John R. Greenland, Marc Hellerstein, Mark Fitch, Kelvin W. Li, Jonathan H. Esensten, Amy L. Putnam, Angela Lares, Vinh Nguyen, Weihong Liu, Nancy D. Bridges, Jonah Odim, Anthony J. Demetris, Josh Levitsky, Timucin Taner, Sandy Feng
Journal: Science Translational Medicine (2022)

Promoting immune tolerance to transplanted organs can minimize the amount of immunosuppressive drugs that patients need to take, reducing lifetime risks of mortality and morbidity. Regulatory T cells (T regs ) are essential for immune tolerance, and preclinical studies have shown their therapeutic efficacy in inducing transplantation tolerance. Here, we report the results of a phase 1/2 trial (ARTEMIS, NCT02474199) of autologous donor alloantigen–reactive T reg (darT reg ) therapy in individuals 2 to 6 years after receiving a living donor liver transplant. The primary efficacy endpoint was calcineurin inhibitor dose reduction by 75% with stable liver function tests for at least 12 weeks. Among 10 individuals who initiated immunosuppression withdrawal, 1 experienced rejection before planned darT reg infusion, 5 received darT regs , and 4 were not infused because of failure to manufacture the minimal infusible dose of 100 × 10 6 cells. darT reg infusion was not associated with adverse events. Two darT reg -infused participants reached the primary endpoint, but an insufficient number of recipients were treated for assessing the efficacy of darT regs . Mechanistic studies revealed generalized T reg activation, senescence, and selective reduction of donor reactivity after liver transplantation. Overall, the ARTEMIS trial features a design concept for evaluating the efficacy of T reg therapy in transplantation. The mechanistic insight gained from the study may help guide the design of future trials.